Synthesis of chamaecypanone C analogues from in situ-generated cyclopentadienones and their biological evaluation

Article abstract of DOI:10.1021/ja3084708

A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated o-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure.

Full text of DOI:10.1021/ja3084708

Article
pubs.acs.org/JACS
Synthesis of Chamaecypanone C Analogues from in Situ-Generated
Cyclopentadienones and Their Biological Evaluation
Suwei Dong,†,∥ Tian Qin,† Ernest Hamel,‡ John A. Beutler,§ and John A. Porco, Jr.*,†
†Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University,
590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
§
‡Screening Technologies Branch and Molecular Targets Laboratory, Frederick National Laboratory for Cancer Research,
National Cancer Institute, Frederick, Maryland 21702, United States
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed dehydrogenation protocol
for the conversion of 3,5-diarylcyclopentenones to the cor-
responding 2,4-diarylcyclopentadienones has been developed.
With this protocol, analogues of the cytotoxic agent chamaecy-
panone C have been synthesized via Diels−Alder cycloaddition
between the cyclopentadienones and in situ-generated o-quinols.
Biological evaluation of these analogues revealed a compound
with higher activity as a microtubule inhibitor and cytotoxic
agent in comparison with the parent structure.
on the synthesis of cycloadducts derived from 2,4-cyclo-
pentadienones with variable aromatic substitution (Scheme 1).
INTRODUCTION
■
Cyclopentadienones are highly reactive and unstable species
and in many cases are known to dimerize readily to release
antiaromaticity.1 As useful synthons, cyclopentadienone and
derivatives have been utilized in both electrocyclic reactions2
and pericyclic additions.3 In these cases, “deantiaromatization”
has been proposed to be a significant driving force. Moreover,
cyclopentadienones have been used as key reagents to access
biologically active natural products, including manzamenone A
(1)4 and chamaecypanone C (2)5,6 (Figure 1).
Scheme 1. Approach to Chamaecypanone C Analogues
Herein we report our studies leading to the development of a
general protocol for the preparation of 2,4-diarylcyclopenta-
dienones en route to chamaecypanone C analogues as well as
the biological evaluation of the target compounds as micro-
tubule inhibitors.
RESULTS AND DISCUSSION
Figure 1. Cyclopentadienone-derived natural products.
■
Syntheses of cyclopentadienones have been achieved using various
protocols, including elimination of bromocyclopentenones8 and
hydroxycyclopentenones,4a,9 condensations of propanones with
α-diketones,10 photochemical decarbonylation11and SO2 ex-
We previously reported the synthesis of the bicyclo[2.2.2]-
octenone-containing natural product (+)-chamaecypanone C (2)
utilizing as the key step a retro-Diels−Alder/Diels−Alder
cascade of a 6-alkyl-6-hydroxycyclohexa-2,4-dienone (o-quinol)
dimer wherein an in situ-generated 2,4-diarylcyclopentadienone
reacted with the o-quinol in a highly diastereoselective
manner.5a The observed reactivity of the diarylcyclopentadienone
reaction partner prompted further study of the key transformation.
Furthermore, on the basis of the demonstrated tubulin inhibitory
activity of chamaecypanone C,5a,7 a general approach to analogues
with modified structures was desirable for further biological
studies, in particular for the evaluation of structure−activity
relationships (SARs). With these considerations in mind, we focused
trusion,12 and carbonylation of metallacyclopentadienes.13
A
recent elegant methodology developed by the Wender group
involves rhodium(I)-catalyzed [3 + 2] cycloaddition of cyclo-
propenones and alkynes.14 In most cases, tri- or tetrasubstituted
cyclopentadienones are produced; mono- or disubstituted
cyclopentadienones are less commonly reported, likely because
of their instability or tendency to dimerize.8c In particular, to
Received: August 26, 2012
Published: October 31, 2012
© 2012 American Chemical Society
19782
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787

Journal of the American Chemical Society
Article
date there are very few reported examples of 2,4-disubstituted
cyclopentadienones15 and no reports of 2,4-diarylcyclopenta-
dienones or derived dimers in the literature.
Scheme 3. Synthetic Routes to Diarylcyclopentenones
As a 2,4-diarylcyclopentadienone is a key precursor to
chamaecypanone C, the preparation of analogues with similar
substitution patterns requires a protocol to access the corresponding
cyclopentadienones. In view of the abundance of the corresponding
cyclopentenone precursors, it should be possible to dehydrogenate
these compounds to obtain the target molecules. In our previous
studies, 2,4-diarylcyclopentenone 3 was used as a substrate under
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-mediated oxidation
conditions (Scheme 2), which generated 2,4-diarylcyclopentadienone
Scheme 2. First-Generation Synthesis of Chamaecypanone C
Table 1. Generation of α-Pyrones from Diarylcyclopentenones
under Aerobic Dehydrogenation Conditions
4 in situ. In the same pot, the thermolytic retro-Diels−Alder
reaction of dimer 5 afforded o-quinol 6, which subsequently
reacted with intermediate 4 to afford chamaecypanone C methyl
ether (7) in a highly diastereoselective manner. Upon treatment
with excess boron tribromide, cycloadduct 7 was demethylated to
afford (+)-chamaecypanone C (2). This synthetic sequence also
represents use of a dehydrogenative Diels−Alder cycloaddition in
natural product synthesis.16
a
In our previous studies we were able to prepare di-p-
methoxyphenyl-substituted cyclopentenone 3 from cyclo-
pentene (8) using a sequence involving double Heck cross-
coupling,17 allylic hydroxylation, and 2-iodoxybenzoic acid (IBX)
oxidation5a (Scheme 3a).5a However, we recognized that this
route may not be optimal for the preparation of diarylcyclo-
pentadienone precursors because of the potential limitation
of aryl substitution and formation of isomerized alkene by-
products in the double Heck reaction as well as the use of
substoichiometric amounts of toxic selenium dioxide in the
allylic oxidation step. Recently Xu, McLaughlin, and co-workers
established a general and scalable method for the preparation of
3,5-diarylcyclopentenones with a broad scope (Scheme 3b).18
We proposed that these cyclopentenones may react similarly to
the corresponding 2,4-diaryl compounds in the dehydrogen-
ative Diels−Alder event. Accordingly, our goal was to identify
suitable reaction conditions to produce cyclopentadienones
from the readily accessible 3,5-diarylcyclopentenones.
Investigation of Aerobic Dehydrogenation. Although
dehydrogenation of ketones using IBX19 or DDQ20 is well-
known, we first focused our attention on the evaluation of
catalytic oxidative conditions to avoid the stoichiometric use
of oxidants.21 With 3,5-diphenylcyclopentenone (9)18 as a
model substrate, representative conditions for catalytic aerobic
dehydrogenation, including Pd(TFA)2/bipyridine/O222 and TiO2-
supported gold nanoparticles (AuNP/TiO2),23 were investigated
(Table 1, entries 1 and 2). Interestingly, instead of the desired
b
c
entry cyclopentenone
catalyst
time (h) yield (%)
1
2
3
4
9
9
Pd(TFA)2/bipyridine
AuNP/TiO2
12
12
12
12
36
80
46
50
11
12
AuNP/TiO2
d
AuNP/TiO2
a
Reaction conditions: 5 mol % catalyst, O2, chlorobenzene, 100 °C.
Pd(TFA)2 = palladium(II) trifluoroacetate; AuNP = gold nano-
particle. Isolated yields after silica gel column chromatography. The
product was inseparable from the starting material, and the yield was
b
c
d
1
based on H NMR integration.
Figure 2. Possible mechanism leading to α-pyrones.
Scheme 4. In Situ Trapping Experiment
19783
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787

Journal of the American Chemical Society
Article
cyclopentadienone, 4,6-diphenyl-α-pyrone (10) was identified as
Two other cyclopentenones, 11 (entry 3) and 12 (entry 4),
were also evaluated under the AuNP-catalyzed oxidation condi-
tions and gave the corresponding 4,6-diaryl-α-pyrones 13 and
14 as the major products.
the major product, and no diarylcyclopentadienone or derived
1
products were produced under the reaction conditions. The H
and 13C NMR spectra for 10 were identical to literature data,24
and the structure was further confirmed by X-ray crystallography.25
A plausible mechanism accounting for the generation of α-pyrone
10 is depicted in Figure 2. Under Pd- or AuNP-catalyzed con-
ditions, aerobic dehydrogenation of 9 should afford cyclo-
pentadienone 15 accompanied by the generation of hydrogen
peroxide.21,26 Because of the instability of 15, the compound
may subsequently react with H2O2 to afford intermediates such
as hydroperoxide 16, thereby releasing antiaromaticity.1 Baeyer−
Villiger-type rearrangement of 16 should then generate 10.27
A literature-reported example of aerobic oxidation of tetraphenylcy-
clopentadienone (tetracyclone) to an α-pyrone under thermolytic
conditions28 also supports the likely intermediacy of cyclo-
pentadienone 15.29 Moreover, treatment of cyclopentenone 9
with 2.0 equiv of H2O2 (dioxane, 80 °C, 16 h) led to no
reaction, indicating that cyclopentadienone formation may be
required prior to Baeyer−Villiger reaction.30
With the hope of intercepting the generated intermediate 15,
we also investigated a one-pot procedure in which a mixture of
cyclopentenone 9 and the readily available dimer ( )-531 was
heated in the presence of a AuNP/TiO2 catalyst under an oxygen
atmosphere. Unfortunately, the reaction afforded a complicated
mixture, and no generation of the desired cycloadduct 17 was
observed (Scheme 4).
Table 2. Reaction Optimization for the Dehydrogenation of
a
Diarylcyclopentenones
b
entry catalyst or oxidant time (h) % conversion to cycloadduct 17
1
2
3
4
5
6
Pd/C
6
6
28
Pt/C
<5
Rh/Al2O3
Rh/C
Rh/C
DDQ
6
<5
16
18
2
56
c
e
d
>95 (81)
33
a
Reaction conditions: 3.0 equiv of 9 (1.5 equiv with respect to
generated o-quinol monomer), 10 mol % catalyst (based on 9),
b
mesitylene, 150 °C, argon atmosphere. Based on 1H NMR
c
integration of dimer 5 and product 17. 5.0 equiv of 9 (2.5 equiv
d
Evaluation of Anaerobic Dehydrogenation Condi-
tions. In view of the reactivity of 2,4-diarylcyclopentadienones
to form byproducts, including α-pyrones under aerobic conditions,
with respect to o-quinol monomer) was used in the reaction. Isolated
e
yield is given in parentheses. 5.0 equiv of 9, 6.0 equiv of DDQ,
o-DCB, 150 °C, argon atmosphere.
a
Table 3. Diels−Alder Cycloadditions of in Situ-Generated o-Quinols and 2,4-Diarylcyclopentadienones
a
b
Reaction conditions: 10 mol % Rh/C (based on cyclopentenone), mesitylene, 150 °C, argon atmosphere. Isolated yields after silica gel
c
chromatography. Full conversion based on cyclopentenone was observed.
19784
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787

Journal of the American Chemical Society
Article
anaerobic dehydrogenation conditions were next investigated.
Inspired by a reported dehydrogenation of arylcyclohexenones
using palladium on carbon (Pd/C),32 we evaluated several metal
catalysts, including Pd(0), Pt(0), and Rh(0), for dehydrogenation
of cyclopentenone 9 under an argon atmosphere at high tem-
peratures. While in these cases no cyclopentadienone was observed
or isolated, we discovered that in the presence of o-quinol dimer 5,
Pd/C successfully catalyzed the dehydrogenation of 9 to afford
the corresponding dienone intermediate; this was reacted with
an in situ-generated o-quinol leading to the formation of the
desired cycloadduct 17 (Table 2, entry 1). Although 9 was com-
pletely consumed after the thermolysis in mesitylene for 6 h,
a large amount of unreacted dimer 5 suggested the presence
of other degradation pathways for 9. When Pt/C or Rh/Al2O3
was used as the catalyst, a complex mixture of products was ob-
tained, including the phenol 3-hydroxy-α,4-dimethylstyrene33,34
(entry 2), or severe decomposition of the starting materials
(entry 3) was observed. After extensive experimentation, reactions
with Rh/C as the catalyst were found to afford the desired [4 + 2]
cycloadduct 17 cleanly (entry 4). As the conversion of o-quinol
dimer 5 was incomplete while all of the cyclopentenone was
consumed, we decided to increase the amount of easily accessed
reaction partner 9. Accordingly, using 5.0 equiv of 9 (2.5 equiv
with respect to o-quinol monomer) and extending the reaction
time led to improved conversion (entry 5), affording product 17
in good yield (81%). The requirement of excess cyclopentenone
may be due to the instability of the generated cyclopentadienone
under the reaction conditions.
investigated as substrates for Rh/C-catalyzed dehydrogenation.
Dimers ( )-20 (Table 4, entry 1) and ( )-21 (entries 2 and 3)
Table 4. Dehydrogenative Cycloadditions Using Alternative
a
Dimers and Cyclopentenones
To evaluate further the efficiency of the Rh-catalyzed de-
hydrogenation relative to our previously developed protocol,5a
DDQ (6.0 equiv) was slowly added to a mixture of dimer 5 and
compound 9 (5.0 equiv) in o-dichlorobenzene (o-DCB) at 150 °C
over a period of 1 h. Further reaction at the same temperature
for an additional 1 h resulted in the generation of cycloadduct
17 with approximately 33% conversion (Table 2, entry 6) along
with a significant amount of unreacted starting material. Attempts
to improve the conversion by extending the reaction time led
to severe decomposition. These results suggested that DDQ-
mediated oxidation is less effective than the Rh-catalyzed protocol
for substrate 9.
Under the optimized conditions, 2,4-diarylcyclopentenone sub-
strates 18a−h were evaluated (Table 3). Substrates with electron-
rich aryl substituents reacted smoothly to afford cycloadducts in
moderate to good yields (entries 1, 2, and 4−6). In the case of
2-chlorophenyl-substituted compound 18c, low conversion was
observed because of its poor solubility, leading to a low isolated
yield of the desired product 19c (entry 3). Reaction with a
substrate bearing a heterocyclic substituent also produced the
[4 + 2] cycloadduct in moderate yield (entry 7). Styrenylcyclo-
pentenone 18h also underwent dehydrogenation under the Rh/C-
catalyzed conditions (entry 8). However, only a small amount of
product 19h was isolated, presumably because of the multiple
reaction sites for the generated cyclopentadienone intermedi-
ate. In all cases, reactions to form [4 + 2] adducts proceeded
with high diastereoselectivity in accordance with previous obser-
vations in our synthesis of chamaecypanone C.5a Endo selectivity
and facial selectivity align well with the observed reactivity of
o-quinols,35 wherein the bulky aromatic substituents are oriented
away from the sterically demanding quaternary center.
a
Reaction conditions: 10 mol % Rh/C (based on cyclopentenone),
b
mesitylene, 150 °C. PMP = p-methoxyphenyl. Isolated yields after
silica gel chromatography.
were found to have similar reactivities in comparison to dimer
5, and cycloadducts 22−24 were prepared in good yields from
3,5-diarylcyclopentenones 18e and 25 and 2,4-diarylcyclopen-
tenone 3, respectively. In contrast, o-quinol dimers ( )-26
(Figure 3) and 27 and MOB dimer 28 did not afford any of the
corresponding desired cycloadducts. In the failed cases, dienone−
phenol rearrangement of the 2,4-cyclohexadienone intermediate
was typically observed.38 The reaction using 5-arylcyclopente-
none 29 and dimer 5 under the rhodium-catalyzed conditions
(entry 4) generated a mixture of two [4 + 2] adducts, 30a and
30b, in good combined yield. The two products were separated
and characterized as isomers derived from reactivity of the
unsubstituted cis-alkene. This result correlates well with the
previously observed higher reactivity of disubstituted cis-alkenes
in cycloaddition reactions with o-quinols.35 The lack of 4-aryl
substitution on the cyclopentadienone appeared to diminish the
steric differentiation resulting from the aryl group and the
tertiary alcohol, thereby leading to the formation of isomeric
cycloadducts.
When 3-arylcyclopentenone 3139 (Figure 3) was used as the
cyclopentadienone precursor, no conversion of either starting
material was observed, which suggests that 5-aryl substitution is
required for successful dehydrogenation. This assumption was
further confirmed by the fact that cyclopentenone 32 was also
To evaluate the scope and limitations of the methodology,
selected o-quinol dimers31,36 and masked o-benzoquinone (MOB)
dimers37 were explored as 2,4-cyclohexadienone precursors.
A number of cyclopentenone and indanone substrates were also
19785
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787

Journal of the American Chemical Society
Article
Table 5. Tubulin Assembly and Growth Inhibitory Activities
of Enantiopure Chamaecypanone Analogues
% inhibition of
inhibition of
tubulin assembly
entry compound IC50 SD (μM)
colchicine binding
SD with 5 μM
inhibitor
NCI-60
mean GI50
(μM)
1
2
3
4
5
(+)-35
(+)-36
(+)-37
(+)-38
(+)-2
2.8 0.4
3.2 0.4
2.4 0.3
1.5 0.01
2.2 0.3
30 0.8
27 0.8
32 0.5
50 2.0
30 4.0
0.55
0.56
0.91
0.18
Figure 3. Methodology limitations.
0.28 (n = 2)
inert under the rhodium-catalyzed dehydrogenation conditions.
Additional attempted experiments using indanones 33 and 34
did not yield any of the desired cycloadducts, and no indenone
formation was observed.
To prepare chamaecypanone C analogues with unprotected
hydroxyl groups, previously prepared cycloadducts with methyl
ethers were submitted to BBr3-mediated demethylation conditions,
and the corresponding hydroxyl products were isolated in mod-
erate to good yields (Figure 4).
that reducing the isopropyl appendage [cf. (+)-2] to a methyl
group [(+)-38] slightly improves the potency of both growth
and tubulin assembly inhibition while a t-Bu group at C-11
(compound 41) completely eliminates the activity.25 While
these differences are modest, it is clear that minor modifications of
the parent structure are tolerated while larger changes are not. The
4′ phenolic group appears to be required as a hydrogen-bond
donor, as the 4′-desoxy analogue 39 and the dimethoxy analogue
19e were found to be inactive.25 The 4″-OH group was found to
be less critical, as both the thiophene analogue (+)-37 (Table 5,
entry 3) and the 4″-desoxy analogue (+)-35 (entry 1) were active.
CONCLUSION
■
We have developed a rhodium-catalyzed anaerobic dehydro-
genation protocol to convert 3,5-diarylcyclopentenones to the
corresponding 2,4-diarylcyclopentadienones. A series of in situ-
generated, highly reactive cyclopentadienones were successfully
utilized to prepare a series of chamaecypanone C analogues via
[4 + 2] cycloaddition with in situ-generated o-quinols. Our
investigation also led to the discovery of a gold-nanoparticle-
catalyzed transformation of 3,5-diarylcyclopentenones to diaryl-
α-pyrones. Initial biological studies of chamaecypanone C ana-
logues uncovered a chamaecypanone C derivative, (+)-38, with
higher activity as a microtubule inhibitor and cytotoxic agent in
comparison with the parent structure. Further biological studies
of chamaecypanone C derivatives, as well as the chemistry of
the chamaecypanone C core structure, are ongoing and will be
reported in due course.
Figure 4. Preparation of chamaecypanone C analogues with
unprotected phenols. Values in parentheses are isolated yields.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds, including X-ray structure analysis of compound
10, X-ray crystallographic data (CIF), and detailed biological
methods and results. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
Biological Studies. We utilized the developed synthetic
route to explore the structure−activity space of (+)-chamae-
cypanone C as a microtubule inhibitor and cytotoxic agent.5a,7
Racemic chamaecypanone C analogues were first evaluated in a
tubulin assembly assay. Diphenyl analogue 17, chlorinated
analogue 19c, and all of the methyl-protected analogues were
found to be inactive,25 while structures 35−38 (Figure 4)
showed good activity. Compounds 39 and 40 were also found
to be inactive. Taking note of the previous finding that the
(+)-enantiomer of chamaecypanone C is active while the
(−)-enantiomer is not, we synthesized the enantiopure versions
of active compounds (+)-35 to (+)-38 and tested them in both
the tubulin assay and in the NCI-60 cell screen along with
(+)-chamaecypanone C (2). As summarized in Table 5, these
compounds were found to have activities comparable to that of
the parent, with chemeacypanone C analogue (+)-38 (entry 4)
showing slightly greater activity as an inhibitor of tubulin
assembly and as a cytotoxic agent in the NCI-60 screen (mean
GI50 = 180 nM) relative to the natural product (+)-2 (entry 5).
These results suggested that the 4-p-hydroxyphenyl group
(Figure 4) is crucial for interactions with tubulin and showed
S
AUTHOR INFORMATION
Corresponding Author
■
porco@bu.edu
Present Address
∥Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for
Cancer Research, 1275 York Avenue, New York, New York 10065,
United States.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the NIH (GM-073855 to J.A.P.) and
the NIGMS CMLD Initiative (P50 GM067041 to J.A.P.) is
■
19786
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787

Journal of the American Chemical Society
Article
(21) For recent examples of Pd-catalyzed α,β-dehydrogenation of
carbonyl compounds, see: (a) Diao, T.; Stahl, S. S. J. Am. Chem. Soc.
2011, 133, 14566. (b) Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci.
2012, 3, 887.
(22) Tokunaga, M.; Harada, S.; Iwasawa, T.; Obora, Y.; Tsuji, Y.
Tetrahedron Lett. 2007, 48, 6860.
(23) Sun, H.; Su, F.; Ni, J.; Cao, Y.; He, H.; Fan, K. Angew. Chem., Int.
Ed. 2009, 48, 4390.
(24) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11, 1623.
(25) See the Supporting Information for detailed experimental data.
(26) For AuNP-catalyzed aerobic oxidation involving hydrogen
peroxide formation, see: Miyamura, H.; Shiramizu, M.; Matsubara, R.;
Kobayashi, S. Chem. Lett. 2008, 37, 360.
(27) For a recent example of heterogeneous catalytic Baeyer−Villiger
oxidation of ketones, see: Jeong, E.-Y.; Ansari, M. B.; Park, S.-E. ACS
Catal. 2011, 1, 855.
(28) (a) Thiemann, T.; Iniesta, J.; Walton, D. J. J. Chem. Res. 2008,
173. For Baeyer−Villiger-type rearrangement of tetracyclone to an
α-pyrone with bis(trimethylsilyl) monoperoxysulfate, see: (b) Adam,
W.; Rodriguez, A. J. Org. Chem. 1979, 44, 4969.
gratefully acknowledged. T.Q. thanks Vertex Pharmaceuticals,
Inc. for a graduate fellowship. This research was also supported
in part by the Intramural Research Program of NIH, National
Cancer Institute, Center for Cancer Research and by the Devel-
opmental Therapeutics Program, Division of Cancer Diagnosis and
Treatment. We thank Drs. Jeffrey Bacon (Boston University) and
Charles Campana (Bruker AXS) for X-ray crystal structure analyses
and Drs. Yingju Xu and Mark McLaughlin (Department of Process
Chemistry, Merck Research Laboratories, Merck & Co., Inc.,
Rahway, NJ) for their kind donation of diarylcyclopentenones.
REFERENCES
■
(1) Ogliaruso, M. A.; Romanelli, M. G.; Becker, E. I. Chem. Rev.
1965, 65, 261.
(2) Harmata, M.; Zheng, P.; Schreiner, P. R.; Navarro-Vaz
́
quez, A.
Angew. Chem., Int. Ed. 2006, 45, 1966.
(3) Harmata, M.; Gomes, M. G. Eur. J. Org. Chem. 2006, 2273.
(4) (a) Al-Busafi, S.; Doncaster, J. R.; Drew, M. G. B.; Regan, A. C.;
Whitehead, R. C. J. Chem. Soc., Perkin Trans. 1 2002, 476. For
isolation, see: (b) Tsukamoto, S.; Takeuchi, S.; Ishibashi, M.;
Kobayashi, J. J. Org. Chem. 1992, 57, 5255.
(5) (a) Dong, S.; Hamel, E.; Bai, R.; Covell, D. G.; Beutler, J. A.;
Porco, J. A., Jr. Angew. Chem., Int. Ed. 2009, 48, 1494. For isolation of
chamaecypanone C, see: (b) Chien, S. C.; Chang, J. Y.; Kuo, C. C.;
Hsieh, C. C.; Yang, N. S.; Kuo, Y. H. Tetrahedron Lett. 2007, 48, 1567.
(6) For other representative examples of the use of cyclo-
pentadienones as building blocks in natural product synthesis, see:
(a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Polo, E.; Simoni,
D. J. Chem. Soc., Chem. Commun. 1984, 1049. (b) Schuda, P. F.;
Phillips, J. L.; Morgan, T. M. J. Org. Chem. 1986, 51, 2742. (c) Takano,
S.; Sato, T.; Inomata, K.; Ogasawara, K. J. Chem. Soc., Chem. Commun.
1991, 462.
(29) In the AuNP-catalyzed oxidation of cyclopentenone 12,
hydroxycyclopentenone 42 was isolated as an intermediate. Dehy-
dration of this compound should lead to cyclopentadienone 43 (cf.
refs 5 and 9).
(30) For a recent report of Sn(IV)-mediated Baeyer−Villiger
reactions using H2O2 as the oxidant at elevated temperature, see:
Corma, A.; Iborra, S.; Mifsud, M.; Renz, M.; Susarte, M. Adv. Synth.
Catal. 2004, 346, 257.
(31) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2008, 130,
2738.
(32) Horning, E. C.; Horning, M. G. J. Am. Chem. Soc. 1947, 69,
1359.
(33) Patwardhan, S. A.; Gupta, A. S. Phytochemistry 1983, 22, 2080.
(34) Phenol byproduct 44 was presumably derived from o-quinol
intermediate 6 through an elimination process:
(7) Hsieh, C.; Kuo, Y.; Kuo, C.; Chen, L.; Cheung, C. A.; Chao, T.;
Lin, C.; Pan, W.; Chien, S.; Chen, T.; Lung, C.; Chang, J. Biochem.
Pharmacol. 2010, 79, 1261.
(8) (a) DePuy, C. H.; Lyons, C. F. Chem. Ind. 1961, 429. (b) DePuy,
C. H.; Isaks, M.; Eilers, K. L.; Morris, G. F. J. Org. Chem. 1964, 29,
3503. For a recent report, see: (c) Harmata, M.; Barnes, C. L.;
Brackley, J.; Bohnert, G.; Kirchhoefer, P.; Kurti, L.; Rashatasakhon, P.
̈
J. Org. Chem. 2001, 66, 5232.
(9) Fuchs, B.; Pasternak, M.; Pazhenchevsky, B. J. Org. Chem. 1981,
46, 2017.
(10) (a) Allen, C. F. H.; VanAllan, J. A. J. Am. Chem. Soc. 1950, 72,
5165. (b) Van Ornum, S. G.; Li, J.; Kubiak, G. G.; Cook, J. M. J. Chem.
Soc., Perkin Trans. 1 1997, 3471. (c) Walsh, C. J.; Mandal, B. K. J. Org.
Chem. 1999, 64, 6102. (d) Moore, J. E.; York, M.; Harrity, J. P. A.
Synlett 2005, 860.
(11) DeSelms, R. C.; Schleigh, W. R. Synthesis 1973, 614.
(12) Ried, W.; Bopp, D.-C. H. Angew. Chem., Int. Ed. Engl. 1977, 16,
653.
(35) Dong, S.; Cahill, K. J.; Kang, M.-I.; Colburn, N. H.; Henrich, C.
J.; Wilson, J. A.; Beutler, J. A.; Johnson, R. P.; Porco, J. A., Jr. J. Org.
Chem. 2011, 76, 8944.
(36) Gagnepain, J.; Castet, F.; Quideau, S. Angew. Chem., Int. Ed.
(13) For a review of reactions of metallacyclodienes with leading
2007, 46, 1533.
references, see: Muller, E. Synthesis 1974, 761.
(14) Wender, P. A.; Paxton, T. J.; Williams, T. J. J. Am. Chem. Soc.
2006, 128, 14814.
(15) Bandyopadhyay, C.; Sur, K. R.; Patra, R. J. Chem. Res., Synop.
2002, 414.
(16) For a recent report of dehydrogenative Diels−Alder cyclo-
additions, see: Stang, E. M.; White, M. C. J. Am. Chem. Soc. 2011, 133,
14892.
(37) Liao, C. C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856 and
references therein.
̈
(38) For a recent review of the dienone−phenol rearrangement, see:
Whiting, D. A. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 3, pp
803−821.
(39) Li, J.-H.; Wang, D.-P.; Xie, Y.-X. Synthesis 2005, 2193.
(17) Prashad, M.; Tomesch, J. C.; Wareing, J. R.; Smith, H. C.;
Cheon, S. H. Tetrahedron Lett. 1989, 30, 2877.
(18) Xu, Y.; McLaughling, M.; Chen, C.; Reamer, R. A.; Dormer, P.
G.; Davies, I. W. J. Org. Chem. 2009, 74, 5100.
(19) Nicolaou, K. C.; Zhong, Y.; Baran, P. S. J. Am. Chem. Soc. 2000,
122, 7596.
(20) (a) Walker, D.; Hiebert, J. D. Chem. Rev. 1967, 67, 153.
(b) Buckle, D. R. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A.), Ed.; Wiley: Chichester, U.K., 1995; Vol. 3, p 1699.
19787
dx.doi.org/10.1021/ja3084708 | J. Am. Chem. Soc. 2012, 134, 19782−19787